Neurons and glial cells arise sequentially from common progenitor cells during vertebrate CNS development. The mechanism that governs the transition of progenitor cell fate from neurogenic to gliogenic can be central to the regulation of neurogenesis and brain circuit formation as it affects not only the number of neurons being produced but also the subsequent events of neural maturation and synaptogenesis. Drugs of abuse have been shown to cause profound defects in brain development and malformation of cerebral cortical cytoarchitecture known to associate with fetal growth suppression and CNS functional deficits later in life. Emerging evidence suggests that cocaine-induced abnormal glial development may contribute to the brain damage associated with drugs of abuse in fetus. Recently, our preliminary studies to define the roles for fibroblast growth factor 15 (FGF15) in neural stem cell growth and differentiation revealed a critical activity for FGF15 in inhibiting astrogliogenesis that in turn controls the timing of the transition from neurogenesis to gliogenesis during cortical development. Fetal exposure to cocaine caused a change in levels of FGF15 expression in the developing forebrain and glial differentiation defect. The overall goal of the present research plan is to test the hypothesis that FGF15 is a key signal regulating the transition from neurogenesis to gliogenesis in the developing cortex and that drugs of abuse may alter FGF15 signaling to cause abnormal astroglial differentiation and subsequent malformation of brain circuits in the forebrain. Aim 1 of this research plan will determine if FGF15 signaling is required and sufficient for inhibiting astrogliogenesis and maintaining neurogenic potential in cortical progenitor cell cultures as well as in FGF15 deficient mice. Aim 2 will investigate whether activation of FGF15 signaling attenuates the intracellular events triggering astrogliogenesis in the developing cortex. The results of this study will not only provide critical insight into the mechanisms controlling neuro- and glio- genesis during brain development but also facilitate a better understanding of the mechanisms of drug abuse and lead to new designs of more effective therapeutics. PUBLIC HEALTH RELEVANCE: A fundamental feature of neural development is that different cell types are generated in a precise sequence-first neurons, followed by astrocytes and then oligodendrocytes. The emerging evidence suggests that abnormalities in astroglial differentiation may be an underlying cause of drugs of abuse-induced brain damage or of other neurodegenerative or developmental disorders. Recent preliminary studies from my laboratory have pointed out a prominent activity of fibroblast growth factor 15 (FGF15) in the regulation of the transition from neurogenesis to gliogenesis during mouse cortical development. In addition, we discovered that fetal exposure to cocaine altered the level of FGF15 expression in the cortex. In the present research plan, we propose to further elucidate the roles of FGF15 in the regulation of cortical progenitor cell fate determination and glial differentiation and to determine whether alterations of FGF15 signaling could be an underlying mechanism associated with cocaine-induced malformation of brain circuits. The results of the proposed studies may provide critical insights into the adaptive processes associated with drug addiction and identify important molecular and cellular targets for pharmacological or gene therapeutic interventions to combat the pathological sequel to drugs of abuse.